Download PDF

Clinical Trial Results:
A Phase1/2, Randomized, Blinded, Placebo controlled, Multiple-ascending-dose Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Overweight and Obese Subjects with a History of Type 2 Diabetes Mellitus

Summary
EudraCT number	2014-003716-36
Trial protocol	DE
Global end of trial date	24 Feb 2017

Results information
Results version number	v1
This version publication date	30 May 2018
First version publication date	30 May 2018
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

D5670C00002

ISRCTN number

US NCT number

NCT02548585

WHO universal trial number (UTN)

Sponsor organisation name

MedImmune, LLC

Sponsor organisation address

Milstein Building, Granta Park, Cambridge, United Kingdom, CB21 6GH

Public contact

Philip Ambery, MedImmune, LLC, +44 1223 895997, information.center@astrazeneca.com

Scientific contact

Philip Ambery, MedImmune, LLC, +44 1223 895997, information.center@astrazeneca.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

24 Feb 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Feb 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to assess the effect of MEDI0382 on glucose control (as measured by the standardized mixed-meal test [MMT] glucose data) and body weight from baseline to the end of a 4-week period at a stable dose.

Protection of trial subjects

The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and were consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Subjects signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Dec 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 113

Worldwide total number of subjects

113

EEA total number of subjects

113

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

104

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

The study was conducted from 09 Dec 2015 to 24 Feb 2017 in Germany.

Screening details

A total of 422 subjects were screened, of which 295 were screen failures and 14 subjects were enrolled but not randomized. A total of 113 subjects were randomized in the study. One subject was randomised but not treated with study drug.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received placebo (matched to either 100 micrograms [mcg], or 150 mcg or 200 mcg or 300 mcg of MEDI0382) subcutaneously (SC) once daily from Day 1 to Day 7 (Cohort 1); or Day 1 to Day 11 (Cohort 2); or Day 1 to Day 15 (Cohort 3); or Day 1 to Day 41 (Cohort 4); or Day 1 to Day 22 (Cohort 5); or Day 1 to Day 17 (Cohort 6).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Sterile solution

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo matched to either 100 mcg, or 150 mcg or 200 mcg or 300 mcg of MEDI0382 was administered subcutaneously (SC) once daily from Day 1 to Day 7 (Cohort 1); or Day 1 to Day 11 (Cohort 2); or Day 1 to Day 15 (Cohort 3); or Day 1 to Day 41 (Cohort 4); or Day 1 to Day 22 (Cohort 5); or Day 1 to Day 17 (Cohort 6).

Cohort 1: MEDI0382 100 mcg

Arm description

Subjects received MEDI0382 100 mcg SC once daily from Day 1 to Day 7.

Arm type

Experimental

Investigational medicinal product name

MEDI0382

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

MEDI0382 100 mcg was administered SC once daily from Day 1 to Day 7.

Cohort 2: MEDI0382 150 mcg

Arm description

Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

Arm type

Experimental

Investigational medicinal product name

MEDI0382

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter an uptitrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

Cohort 3: MEDI0382 200 mcg

Arm description

Arm type

Experimental

Investigational medicinal product name

MEDI0382

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 4: MEDI0382 200 mcg

Arm description

Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12), then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).

Arm type

Experimental

Investigational medicinal product name

MEDI0382

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter an uptitrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by a second uptitrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12); then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).

Cohort 5: MEDI0382 300 mcg

Arm description

Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22).

Arm type

Experimental

Investigational medicinal product name

MEDI0382

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter an uptitrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second uptitrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third uptitrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22). for 4 days (Day 9 to Day 12); then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).

Cohort 6: MEDI0382 300 mcg

Arm description

Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17).

Arm type

Experimental

Investigational medicinal product name

MEDI0382

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter an uptitrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second uptitrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17).

Number of subjects in period 1 ^[1]	Placebo	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg
Started	45	6	6	7	25	11	12
Completed	43	6	6	5	22	10	11
Not completed	2	0	0	2	3	1	1
Consent withdrawn by subject	-	-	-	-	-	1	-
Not Specified	1	-	-	2	3	-	1
Lost to follow-up	1	-	-	-	-	-	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Total subjects enrolled worldwide were 113; of which 1 subject was randomized but not treated. This 1 subject was not included in As-treated population and data for the subject was not captured for baseline characteristics.

Baseline characteristics

Top of page

Reporting group title

Placebo

Reporting group description

Reporting group title

Cohort 1: MEDI0382 100 mcg

Reporting group description

Subjects received MEDI0382 100 mcg SC once daily from Day 1 to Day 7.

Reporting group title

Cohort 2: MEDI0382 150 mcg

Reporting group description

Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

Reporting group title

Cohort 3: MEDI0382 200 mcg

Reporting group description

Reporting group title

Cohort 4: MEDI0382 200 mcg

Reporting group description

Reporting group title

Cohort 5: MEDI0382 300 mcg

Reporting group description

Reporting group title

Cohort 6: MEDI0382 300 mcg

Reporting group description

Reporting group values	Placebo	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Total
Number of subjects	45	6	6	7	25	11	12	112
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0
Adults (18-64 years)	42	4	6	7	23	10	11	103
From 65-84 years	3	2	0	0	2	1	1	9
85 years and over	0	0	0	0	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	57.2 ( 6.0 )	62.5 ( 2.9 )	60.2 ( 4.2 )	57.0 ( 4.9 )	56.0 ( 7.2 )	54.8 ( 6.8 )	54.6 ( 6.5 )	-
Sex: Female, Male
Units: Subjects
Male	27	5	2	5	13	7	9	68
Female	18	1	4	2	12	4	3	44
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0
Black or African American	1	0	0	0	0	0	0	1
White	44	6	6	7	25	11	12	111
More than one race	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0	0	0
Not Hispanic or Latino	45	6	6	7	25	11	12	112
Unknown or Not Reported	0	0	0	0	0	0	0	0

End points

Top of page

Reporting group title

Placebo

Reporting group description

Reporting group title

Cohort 1: MEDI0382 100 mcg

Reporting group description

Subjects received MEDI0382 100 mcg SC once daily from Day 1 to Day 7.

Reporting group title

Cohort 2: MEDI0382 150 mcg

Reporting group description

Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

Reporting group title

Cohort 3: MEDI0382 200 mcg

Reporting group description

Reporting group title

Cohort 4: MEDI0382 200 mcg

Reporting group description

Reporting group title

Cohort 5: MEDI0382 300 mcg

Reporting group description

Reporting group title

Cohort 6: MEDI0382 300 mcg

Reporting group description

Subject analysis set title

Cohort 4: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 4 days (Day 9 to Day 12), then a further placebo (matched to MEDI0382 200 mcg) SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by placebo (matched to MEDI0382 200 mcg) SC once daily for 1 day in hospital (Day 41).

Subject analysis set title

Cohort 1: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received placebo matched to (MEDI0382 100 mcg) SC once daily from Day 1 to Day 7.

Subject analysis set title

Cohort 2: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 7 days (Day 5 to Day 11).

Subject analysis set title

Cohort 3: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Participants received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 7 days (Day 9 to Day 15).

Subject analysis set title

Cohort 5: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received placebo (matched to MEDI0382 100 mcg ) SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of placebo (matched to MEDI0382 300 mcg) SC once daily for 7 days (Day 16 to Day 22).

Subject analysis set title

Cohort 6: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of placebo (matched to MEDI0382 300 mcg) SC once daily for 7 days (Day 11 to Day 17).

Primary: Percent Change From Baseline in Mixed-meal Test (MMT) Glucose Area Under the Concentration-time Curve From Time 0 to 4 hours to the End of Treatment (EOT) (Cohort 4)

Top of page

End point title

Percent Change From Baseline in Mixed-meal Test (MMT) Glucose Area Under the Concentration-time Curve From Time 0 to 4 hours to the End of Treatment (EOT) (Cohort 4) ^[1]

End point description

Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hours (hrs) after consumption of the standardized meal (with no additional food intake during this time). Pharmacodynamic (PD) population was analysed for this end point, which included all subjects who received at least 1 dose of study drug and had at least 1 post-MMT PD blood sample.

End point type

Primary

End point timeframe

Baseline (Day -1) and EOT (Day 41)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 4: MEDI0382 200 mcg	Cohort 4: Placebo
Number of subjects analysed	25	26
Units: hourmilligrams per deciliter (hrmg/dL)
arithmetic mean (standard deviation)	-33.81 ( 18.62 )	-9.24 ( 12.30 )

Statistical analysis 1

Comparison groups

Cohort 4: MEDI0382 200 mcg v Cohort 4: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

ANCOVA

Confidence interval

Notes
[2] - p-value was based on pairwise comparison using analysis of covariance (ANCOVA) adjusted by baseline value.

Primary: Change From Baseline in Body Weight to the EOT (Cohort 4)

Top of page

End point title

Change From Baseline in Body Weight to the EOT (Cohort 4) ^[3]

End point description

Intent-to-treat (ITT) population was analysed for this end point, which included all subjects who were randomised and received any study drug and analysed according to the initial randomisation.

End point type

Primary

End point timeframe

Baseline (Day 1) and EOT (Day 42)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 4: MEDI0382 200 mcg	Cohort 4: Placebo
Number of subjects analysed	25	26
Units: Kilograms (Kg)
arithmetic mean (standard deviation)	-3.83 ( 2.09 )	-1.71 ( 2.10 )

Statistical analysis 1

Comparison groups

Cohort 4: MEDI0382 200 mcg v Cohort 4: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008 ^[4]

Method

ANCOVA

Confidence interval

Notes
[4] - p-value was based on pairwise comparison using ANCOVA adjusted by baseline value.

Secondary: Percent Change From Baseline in MMT Glucose AUC0-4h to the EOT (Cohorts 1, 2, 3, 5, and 6)

Top of page

End point title

Percent Change From Baseline in MMT Glucose AUC0-4h to the EOT (Cohorts 1, 2, 3, 5, and 6) ^[5]

End point description

Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.

End point type

Secondary

End point timeframe

Cohort 1: Baseline (Day -1) to EOT ( Day 7); Cohort 2: Baseline (Day -1) to EOT (Day 11); Cohort 3: Baseline (Day -1) to EOT (Day 15); Cohort 5: Baseline (Day -1) to EOT (Day 22); Cohort 6: Baseline (Day -1) to EOT (Day 17)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	11	12	3	3	3	5	5
Units: hr*mg/dL
arithmetic mean (standard deviation)	-41.80 ( 11.07 )	-36.73 ( 10.09 )	-39.58 ( 5.27 )	-41.66 ( 9.97 )	-38.19 ( 12.51 )	-14.60 ( 5.56 )	-15.07 ( 13.46 )	-0.47 ( 15.16 )	-14.52 ( 8.12 )	-4.80 ( 3.45 )

No statistical analyses for this end point

Secondary: Change From Baseline in Body Weight to the EOT (Cohorts 1, 2, 3, 5, and 6)

Top of page

End point title

Change From Baseline in Body Weight to the EOT (Cohorts 1, 2, 3, 5, and 6) ^[6]

End point description

ITT population was analysed for this end point. Subjects who did not complete the treatment were not included in this analysis.

End point type

Secondary

End point timeframe

Cohort 1: Baseline (Day 1) to EOT (Day 8); Cohort 2: Baseline (Day 1) to EOT (Day 12); Cohort 3: Baseline (Day 1) to EOT (Day 16); Cohort 5: Baseline (Day 1) to EOT (Day 22); Cohort 6: Baseline (Day 1) to EOT (Day 17)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	11	12	3	3	3	5	5
Units: Kg
arithmetic mean (standard deviation)	-2.32 ( 1.29 )	-1.52 ( 0.57 )	-4.63 ( 1.98 )	-3.26 ( 1.99 )	-2.04 ( 1.52 )	-1.20 ( 0.44 )	-1.00 ( 1.13 )	-2.90 ( 1.05 )	-0.98 ( 2.12 )	-0.94 ( 3.09 )

No statistical analyses for this end point

Secondary: Change From Baseline in Hemoglobin A1c (HbA1c) to the EOT (Cohorts 4, 5, and 6)

Top of page

End point title

Change From Baseline in Hemoglobin A1c (HbA1c) to the EOT (Cohorts 4, 5, and 6) ^[7]

End point description

ITT population was analysed for this end point. Subjects who did not complete the treatment were not included in this analysis.

End point type

Secondary

End point timeframe

Cohort 4: Baseline (Day -2) to EOT (Day 42); Cohort 5: Baseline (Day -2) to EOT (Day 22); Cohort 6: Baseline (Day -2) to EOT (Day 17)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	25	11	12	26	5	5
Units: Percent
arithmetic mean (standard deviation)	-0.92 ( 0.41 )	-0.55 ( 0.35 )	-0.42 ( 0.27 )	-0.58 ( 0.30 )	-0.10 ( 0.29 )	-0.18 ( 0.19 )

No statistical analyses for this end point

Secondary: Change From Baseline in Fructosamine to the EOT (Cohorts 4, 5, and 6)

Top of page

End point title

Change From Baseline in Fructosamine to the EOT (Cohorts 4, 5, and 6) ^[8]

End point description

ITT population was analysed for this end point. Subjects who did not complete the treatment were not included in this analysis.

End point type

Secondary

End point timeframe

Cohort 4: Baseline (Day -2) to EOT (Day 41); Cohort 5: Baseline (Day -2) to EOT (Day 22); Cohort 6: Baseline (Day -2) to EOT (Day 17)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	25	11	12	26	5	5
Units: micromol/L
arithmetic mean (standard deviation)	-67.9 ( 44.4 )	-47.4 ( 15.7 )	-47.5 ( 55.3 )	-33.7 ( 44.6 )	-27.8 ( 25.8 )	-48.8 ( 43.7 )

No statistical analyses for this end point

Secondary: Change From Baseline in Fasting Glucose prior to MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Change From Baseline in Fasting Glucose prior to MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6) ^[9]

End point description

Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.

End point type

Secondary

End point timeframe

Cohort 1: Baseline (Day-1) to EOT (Day7); Cohort 2: Baseline (Day-1) to EOT (Day11); Cohort 3: Baseline (Day-1) to EOT (Day15); Cohort 4: Baseline (Day-1) to EOT (Day41); Cohort 5: Baseline (Day-1) to EOT (Day22); Cohort 6: Baseline (Day-1) to EOT (Day17)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	25	11	12	26	3	3	3	5	5
Units: mg/dL
arithmetic mean (standard deviation)	-74.48 ( 24.59 )	-54.06 ( 19.51 )	-63.67 ( 11.93 )	-50.62 ( 33.61 )	-54.42 ( 19.75 )	-55.21 ( 31.13 )	-18.52 ( 18.88 )	-32.44 ( 17.19 )	-49.86 ( 23.24 )	-4.20 ( 33.73 )	-32.08 ( 17.49 )	-16.58 ( 12.45 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Glucose Area Under the Concentration-time Curve From Time 0 to 24 hours (AUC0-24h) after MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Percent Change From Baseline in Glucose Area Under the Concentration-time Curve From Time 0 to 24 hours (AUC0-24h) after MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6) ^[10]

End point description

Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.

End point type

Secondary

End point timeframe

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	25	11	12	26	3	3	3	5	5
Units: hr*mg/dL
arithmetic mean (standard deviation)	-28.34 ( 13.52 )	-29.32 ( 17.24 )	-27.07 ( 10.82 )	-13.50 ( 18.19 )	-34.51 ( 11.25 )	-26.95 ( 9.45 )	-1.06 ( 11.47 )	-21.80 ( 1.41 )	0.80 ( 39.55 )	-13.80 ( 15.95 )	-4.20 ( 28.58 )	-10.10 ( 14.69 )

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Top of page

End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) ^[11]

End point description

An Adverse Event (AE) is any unfavourable and unintended sign, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. Serious adverse events (SAE) is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs and TESAEs are defined as AEs and SAEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). As-treated Population (ATP) was analysed for this end point, which included all subjects who received any study drug and analysed according to the treatment they actually received.

End point type

Secondary

End point timeframe

From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	25	11	12	26	3	3	3	5	5
Units: Subjects
TEAEs	6	5	7	22	10	10	23	2	3	3	4	2
TESAEs	0	0	1	0	0	0	1	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Abnormal Vital Signs and Physical Examination Reported as TEAEs

Top of page

End point title

Number of Subjects With Abnormal Vital Signs and Physical Examination Reported as TEAEs ^[12]

End point description

TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of subjects with TEAEs related to vital signs and physical examination abnormalities were reported. As-treated population was analysed for this end point.

End point type

Secondary

End point timeframe

From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	25	11	12	26	3	3	3	5	5
Units: Subjects
Blood Pressure increased	0	0	0	1	0	0	2	0	0	0	0	0
Blood pressure systolic increased	0	0	0	0	1	0	0	0	0	0	0	1
Blood pressure diastolic increased	0	0	0	0	0	1	0	0	0	0	0	0
Physical Examinations	0	0	0	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Abnormal 12 Lead Electrocardiogram (ECG) Reported as TEAEs

Top of page

End point title

Number of Subjects With Abnormal 12 Lead Electrocardiogram (ECG) Reported as TEAEs ^[13]

End point description

TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of subjects with TEAEs related to ECG abnormalities were reported. As-treated population was analysed for this end point.

End point type

Secondary

End point timeframe

From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	25	11	12	26	3	3	3	5	5
Units: Subjects
Arrhythmia	1	0	0	0	0	0	0	0	0	0	0	0
Atrial fibrillation	0	0	0	1	0	0	0	0	0	0	0	0
Atrioventricular block first degree	1	0	0	0	0	0	0	0	0	0	0	0
Atrioventricular block second degree	1	0	0	0	0	0	0	0	0	0	0	0
Electrocardiogram ST segment depression	0	0	1	0	0	0	0	0	0	0	0	0
Extrasystoles	0	0	0	0	0	0	0	0	1	1	0	0
Sinus tachycardia	0	0	0	1	0	0	0	0	0	0	0	0
Supraventricular extrasystoles	0	0	0	0	0	0	1	0	0	0	0	0
Supraventricular tachycardia	1	0	1	0	0	0	0	1	1	1	0	0
Tachycardia	1	1	1	0	0	0	0	0	0	0	0	0
Ventricular extrasystoles	1	1	0	1	0	0	1	0	1	0	0	0
Ventricular tachycardia	0	0	1	0	0	0	0	0	0	1	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Abnormal Clinical Laboratory Reported as TEAEs

Top of page

End point title

Number of Subjects With Abnormal Clinical Laboratory Reported as TEAEs ^[14]

End point description

TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of subjects with TEAEs related to laboratory abnormalities were reported. As-treated population was analysed for this end point.

End point type

Secondary

End point timeframe

From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	25	11	12	26	3	3	3	5	5
Units: Subjects
Lipase increased	0	1	0	1	2	1	0	0	0	0	0	0
Hypokalemia	0	0	0	1	0	1	1	0	0	0	0	0
C-reactive protein increased	0	0	1	0	0	0	0	0	0	0	0	0
Hypoglycemia	0	0	0	1	0	0	0	0	0	0	0	0
Chromaturia	0	0	0	1	1	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Any Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score (Cohorts 4, 5, and 6)

Top of page

End point title

Number of Subjects With Any Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score (Cohorts 4, 5, and 6) ^[15]

End point description

The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behaviour of subjects. Yes/No responses are mapped to C-SSRS to assess whether subject experienced suicidal behaviour and suicidal ideation. Suicidal behaviour questions includes preparatory acts or behaviour, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation questions includes wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intent to act, active suicidal ideation with some intent to act (without specific plan), and active suicidal ideation with specific plan and intent. Subjects with yes response to any category for suicidal ideation were reported. As-treated population was used for analysis. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was evaluable for specified time point.

End point type

Secondary

End point timeframe

Cohort 4: Day -1, and Days 13, 20, 27, 34, and 40; Cohort 5: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 36 days); Cohort 6: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 31 days)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	25	11	12	26	5	5
Units: Subjects
Day -1 (n = 25, 11, 12, 26, 5, 5)	4	2	2	1	0	0
Day 13 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	1	99999	99999
Day 20 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	0	99999	99999
Day 27 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	0	99999	99999
Day 34 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	0	99999	99999
Day 40 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	0	99999	99999
Days 7-14 post last dose (n = 0, 11, 12, 0, 5, 5)	99999	1	0	99999	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Any Suicidal Behaviour as Assessed by C-SSRS Score (Cohorts 4, 5, and 6)

Top of page

End point title

Number of Subjects With Any Suicidal Behaviour as Assessed by C-SSRS Score (Cohorts 4, 5, and 6) ^[16]

End point description

End point type

Secondary

End point timeframe

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	25	11	12	26	5	5
Units: Subjects
Day -1 (n = 25, 11, 12, 26, 5, 5)	2	1	1	2	0	0
Day 13 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	1	99999	99999
Day 20 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	0	99999	99999
Day 27 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	0	99999	99999
Day 34 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	0	99999	99999
Day 40 (n = 25, 0, 0, 26, 0, 0)	0	99999	99999	0	99999	99999
Days 7-14 post last dose (n = 0, 11, 12, 0, 5, 5)	99999	0	0	99999	0	0

No statistical analyses for this end point

Secondary: Terminal Elimination Half Life (t1/2) of MEDI0382 (Cohorts 1, 2, and 3)

Top of page

End point title

Terminal Elimination Half Life (t1/2) of MEDI0382 (Cohorts 1, 2, and 3) ^[17]

End point description

Terminal elimination half Life is the time measured for the plasma concentration of MEDI0382 to decrease by one half. Pharmacokinetic (PK) population was analysed for this end point, which included all subjects who received at least 1 dose of study drug and had at least one PK sample taken that was above the lower limit of quantitation. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was analysed for the specified time points. 95% confidence interval (CI) data was not applicable as only one subject was evaluable; therefore, lower and upper CI values are presented with arbitrary values of '0.999999' and '99.9999', respectively for the specified time points.

End point type

Secondary

End point timeframe

Cohort (C) 1 (Day [D] 1 and [&] D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose; and additional 48 hr post C1D7, C2D11, C3D15 dose

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg
Number of subjects analysed	6	6	7
Units: hr
geometric mean (confidence interval 95%)
Day 1 (n = 1, 0, 0)	8.5 (0.999999 to 99.9999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 5 (n = 0, 2, 0)	99999 (99999 to 99999)	10.3 (7.8 to 13.5)	99999 (99999 to 99999)
Day 7 (n = 3, 0, 0)	11.7 (5.5 to 25.1)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 9 (n = 0, 0, 1)	99999 (99999 to 99999)	99999 (99999 to 99999)	8.3 (0.999999 to 99.9999)
Day 11 (n = 0, 6, 0)	99999 (99999 to 99999)	11.3 (5.9 to 21.7)	99999 (99999 to 99999)
Day 15 (n = 0, 0, 5)	99999 (99999 to 99999)	99999 (99999 to 99999)	11.3 (8.2 to 15.5)

No statistical analyses for this end point

Secondary: Accumulation Ratio (Rac) of MEDI0382 (Cohorts 1, 2, and 3)

Top of page

End point title

Accumulation Ratio (Rac) of MEDI0382 (Cohorts 1, 2, and 3) ^[18]

End point description

Accumulation ratio was calculated as, Rac obtained from area under the curve from time zero to end of dosing interval (AUC[0-tau]) of Nth day divided by AUC(0-tau) of Day 1. PK population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was evaluable for the specified time points and arbitrary value '999999' signifies data not reported, since accumulation ratio as described by the formula could not be derived for Cohort 1 Day 1, Cohort 2 Day 5, and for Cohort 3 Day 9.

End point type

Secondary

End point timeframe

C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose; and additional 48 hr post C1D7, C2D11, C3D15 dose

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg
Number of subjects analysed	6	6	7
Units: Ratio
geometric mean (confidence interval 95%)
Day 1 (n = 6, 0, 0)	999999 (999999 to 999999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 5 (n = 0, 6, 0)	99999 (99999 to 99999)	999999 (999999 to 999999)	99999 (99999 to 99999)
Day 7 (n = 6, 0, 0)	1.3 (1.1 to 1.5)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 9 (n = 0, 0, 6)	99999 (99999 to 99999)	99999 (99999 to 99999)	999999 (999999 to 999999)
Day 11 (n = 0, 6, 0)	99999 (99999 to 99999)	1.1 (0.9 to 1.8)	99999 (99999 to 99999)
Day 15 (n = 0, 0, 5)	99999 (99999 to 99999)	99999 (99999 to 99999)	1.3 (1.1 to 1.5)

No statistical analyses for this end point

Secondary: Area Under the Concentration Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Area Under the Concentration Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) ^[19]

End point description

End point type

Secondary

End point timeframe

C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg
Number of subjects analysed	6	6	7	25	11	12
Units: ng*hr/mL
geometric mean (confidence interval 95%)
Day 1 (n = 6, 0, 0, 0, 0, 0)	82.21 (44.56 to 151.69)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 5 (n = 0, 6, 0, 0, 0, 0)	99999 (99999 to 99999)	174.58 (87.41 to 348.67)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 7 (n = 6, 0, 0, 0, 0, 0)	107.01 (54.10 to 211.64)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 9 (n = 0, 0, 4, 23, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	194.78 (146.17 to 259.56)	164.05 (42.67 to 630.76)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 11 (n = 0, 6, 0, 0, 0, 11)	99999 (99999 to 99999)	157.31 (82.45 to 421.12)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	275.29 (169.33 to 447.48)
Day 15 (n = 0, 0, 5, 0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	195.40 (89.8 to 425.17)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 16 (n = 0, 0, 0, 0, 11, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	261.90 (166.58 to 411.74)	99999 (99999 to 99999)
Day 17 (n = 0, 0, 0, 0, 0, 11)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	246.06 (130.34 to 464.51)
Day 22 (n = 0, 0, 0, 0, 10, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	254.35 (196.10 to 329.9)	99999 (99999 to 99999)
Day 41 (n = 0, 0, 0, 22, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	199.10 (84.57 to 468.75)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - inf)] of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - inf)] of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) ^[20]

End point description

PK population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was analysed for the specified time points. 95% CI data was not applicable as only one subject was evaluable; therefore, lower and upper CI values are presented with arbitrary values of '9.99999' and '999.999', respectively for the specified time points.

End point type

Secondary

End point timeframe

C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg
Number of subjects analysed	6	6	7	25	11	12
Units: ng*hr/mL
geometric mean (confidence interval 95%)
Day 1 (n = 1, 0, 0, 0, 0, 0)	103.46 (9.99999 to 999.999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 5 (n = 0, 2, 0, 0, 0, 0)	99999 (99999 to 99999)	207.15 (11.98 to 3580.41)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 7 (n = 3, 0, 0, 0, 0, 0)	184.68 (107.76 to 316.51)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 9 (n = 0, 0, 1, 13, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	242.60 (9.99999 to 999.999)	238.22 (80.99 to 700.67)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 11 (0, 6, 0, 0, 0, 0)	99999 (99999 to 99999)	215.80 (112.90 to 412.47)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 15 (n = 0, 0, 5, 0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	271.84 (119.33 to 619.24)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 16 (n = 0, 0, 0, 0, 6, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	317.93 (182.24 to 554.64)	99999 (99999 to 99999)
Day 17 (n = 0, 0, 0, 0, 0, 4)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	327.28 (249.98 to 428.49)
Day 22 (n = 0,0, 0, 0, 4, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	294.60 (172.52 to 503.05)	99999 (99999 to 99999)
Day 41 (n = 0, 0, 0, 11, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	262.17 (99.79 to 688.77)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Maximum Observed Plasma Concentration (Cmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) ^[21]

End point description

End point type

Secondary

End point timeframe

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg
Number of subjects analysed	6	6	7	25	11	12
Units: ng/mL
geometric mean (confidence interval 95%)
Day 1 (n = 6, 0, 0, 0, 0, 0)	4.97 (0.33 to 7.41)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 5 (n = 0, 6, 0, 0, 0,0)	99999 (99999 to 99999)	9.66 (4.68 to 19.95)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 7 (n = 6, 0, 0, 0, 0, 0)	6.26 (3.36 to 11.67)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 9 (n = 0, 0, 6, 23, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	10.57 (6.33 to 17.66)	11.64 (3.16 to 42.94)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 11 (n = 0, 6, 0, 0, 0, 11)	99999 (99999 to 99999)	9.57 (4.63 to 19.79)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	13.69 (5.73 to 32.71)
Day 15 (n = 0, 0, 5, 0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	10.97 (4.62 to 26.06)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 16 (n = 0, 0, 0, 0, 11, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	17.65 (8.82 to 35.29)	99999 (99999 to 99999)
Day 17 (n = 0, 0, 0, 0, 0, 11)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	15.55 (7.55 to 32.01)
Day 22 (n = 0, 0, 0, 0, 10, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	15.77 (10.02 to 24.8)	99999 (99999 to 99999)
Day 41 (n = 0, 0, 0, 22, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	13.42 (4.77 to 37.75)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Minimum Observed Plasma Concentration (Cmin) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Minimum Observed Plasma Concentration (Cmin) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) ^[22]

End point description

End point type

Secondary

End point timeframe

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg
Number of subjects analysed	6	6	7	25	11	12
Units: ng/mL
geometric mean (confidence interval 95%)
Day 1 (n = 6, 0, 0, 0, 0, 0)	0.705 (0.33 to 1.49)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 5 (n = 0, 6, 0, 0, 0, 0)	99999 (99999 to 99999)	2.685 (1.06 to 6.79)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 7 (n = 6, 0, 0, 0, 0, 0)	2.372 (1.18 to 4.78)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 9 (n = 0, 0, 6, 23, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	3.521 (2.16 to 5.75)	2.635 (0.79 to 8.83)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 11 (n = 0, 6, 0, 0, 0, 11)	99999 (99999 to 99999)	3.59 (1.62 to 7.94)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	3.586 (1.45 to 8.88)
Day 15 (n = 0, 0, 5, 0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	4.973 (2.24 to 11.05)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 16 (n = 0, 0, 0, 0, 11, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	4.062 (1.68 to 9.84)	99999 (99999 to 99999)
Day 17 (n = 0, 0, 0, 0, 0, 11)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	4.766 (2.74 to 8.3)
Day 22 (n = 0, 0, 0, 0, 10, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	5.21 (1.97 to 13.81)	99999 (99999 to 99999)
Day 41 (n = 0, 0, 0, 22, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	3.378 (1.03 to 11.04)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) ^[23]

End point description

End point type

Secondary

End point timeframe

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg
Number of subjects analysed	6	6	7	25	11	12
Units: hr
median (full range (min-max))
Day 1 (n = 6, 0, 0, 0, 0, 0)	8 (6 to 8)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 5 (0, 6, 0, 0, 0, 0)	99999 (99999 to 99999)	6 (4 to 8)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 7 (n = 6, 0, 0, 0, 0, 0)	6 (4 to 6)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 9 (n = 0, 0, 6, 23, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	6 (6 to 8)	4 (1 to 6)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 11 (n = 0, 6, 0, 0, 0, 11)	99999 (99999 to 99999)	6 (4 to 6)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	6 (4 to 12)
Day 15 (n = 0, 0, 5, 0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	6 (4 to 8)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Day 16 (n = 0, 0, 0, 0, 11, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	4 (2 to 8)	99999 (99999 to 99999)
Day 17 (n = 0, 0, 0, 0, 0, 11)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	4 (2 to 6)
Day 22 (n = 0, 0, 0, 0, 10, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	4 (4 to 8)	99999 (99999 to 99999)
Day 41 (n = 0, 0, 0, 22, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	4 (4 to 8)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Number of Subjects With Positive Anti-drug Antibodies to MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Number of Subjects With Positive Anti-drug Antibodies to MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) ^[24]

End point description

As-treated population was analysed for this end point.

End point type

Secondary

End point timeframe

Day 1 up to 7-14 days post-last dose of MEDI0382 for all cohorts (Approximately 60 days)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	25	11	12	26	3	3	3	5	5
Units: Subjects	0	0	0	0	0	0	0	0	1	0	0	0

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Insulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Top of page

End point title

Percent Change From Baseline in Insulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, 4, 5, and 6) ^[25]

End point description

Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.

End point type

Secondary

End point timeframe

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo	Cohort 5: Placebo	Cohort 6: Placebo
Number of subjects analysed	6	6	7	25	11	12	26	3	3	3	5	5
Units: hr*milliunits/L
arithmetic mean (standard deviation)	-9.37 ( 29.17 )	36.32 ( 35.21 )	-17.47 ( 38.84 )	-1.17 ( 44.20 )	1.01 ( 31.00 )	-7.72 ( 37.03 )	-8.63 ( 32.33 )	10.83 ( 21.33 )	-3.67 ( 13.76 )	-20.43 ( 68.82 )	-17.70 ( 16.47 )	-8.18 ( 28.34 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Proinsulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Top of page

End point title

Percent Change From Baseline in Proinsulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4) ^[26]

End point description

Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.

End point type

Secondary

End point timeframe

Cohort 1: Baseline (Day -1) and EOT (Day 7); Cohort 2: Baseline (Day -1) and EOT (Day 11); Cohort 3: Baseline (Day -1) and EOT (Day 15); Cohort 4: Baseline (Day -1) and EOT (Day 41)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo
Number of subjects analysed	6	6	7	25	26	3	3	3
Units: hr*pmol/L
arithmetic mean (standard deviation)	-52.10 ( 36.29 )	-36.77 ( 19.62 )	-54.13 ( 26.40 )	-47.93 ( 22.12 )	-29.72 ( 31.13 )	-3.27 ( 38.92 )	-33.13 ( 40.07 )	81.27 ( 77.21 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in C-peptide AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Top of page

End point title

Percent Change From Baseline in C-peptide AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4) ^[27]

End point description

Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.

End point type

Secondary

End point timeframe

Cohort 1: Baseline (Day -1) and EOT (Day 7), Cohort 2: Baseline (Day -1) and EOT (Day 11), Cohort 3: Baseline (Day -1) and EOT (Day 15); Cohort 4: Baseline (Day -1) and EOT (Day 41)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo
Number of subjects analysed	6	6	7	25	26	3	3	3
Units: hr*nmol/L
arithmetic mean (standard deviation)	-3.82 ( 21.29 )	39.78 ( 32.88 )	-9.07 ( 27.27 )	15.66 ( 42.35 )	8.08 ( 32.12 )	10.17 ( 5.05 )	-1.43 ( 6.02 )	79.37 ( 91.56 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Incretin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Top of page

End point title

Percent Change From Baseline in Incretin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4) ^[28]

End point description

Mixes-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). Incretins included glucagon-like peptide-1 (GLP-1; active and inactive both), glucagon, and gastric inhibitory peptide (GIP). PD population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified parameters. Arbitrary value '999999' signifies standard deviation not applicable as only one subject was evaluable for the specified parameter.

End point type

Secondary

End point timeframe

Cohort 1: Baseline (Day -1) and EOT (Day 7), Cohort 2: Baseline (Day -1) and EOT (Day 11), Cohort 3: Baseline (Day -1) and EOT (Day 15); Cohort 4: Baseline (Day -1) and EOT (Day 41)

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	Cohort 1: MEDI0382 100 mcg	Cohort 2: MEDI0382 150 mcg	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 4: Placebo	Cohort 1: Placebo	Cohort 2: Placebo	Cohort 3: Placebo
Number of subjects analysed	6	6	7	25	26	3	3	3
Units: hr*ng/L
arithmetic mean (standard deviation)
GLP-1, Active: Change at EOT (n=6,6,5,19,2,3,3,24)	-33.67 ( 16.84 )	-50.45 ( 12.30 )	-40.36 ( 26.90 )	-49.73 ( 22.88 )	1.63 ( 26.43 )	8.30 ( 13.15 )	-10.40 ( 10.47 )	-2.87 ( 20.32 )
GLP-1, Inactive:Change at EOT (n=1,3,3,8,1,1,2,14)	0.70 ( 99999 )	-10.93 ( 22.36 )	-8.07 ( 11.30 )	-28.85 ( 16.73 )	3.99 ( 29.59 )	-20.30 ( 99999 )	-22.90 ( 99999 )	1.75 ( 29.20 )
Glucagon: Change at EOT (n=4,5,2,12,2,3,3,18)	-20.25 ( 25.45 )	-38.12 ( 16.33 )	-3.05 ( 36.56 )	-30.17 ( 25.56 )	-1.76 ( 21.47 )	-13.85 ( 18.60 )	-17.53 ( 19.46 )	-18.73 ( 21.59 )
GIP: Change at EOT (n=2,5,5,12,2,2,2,17)	-46.50 ( 14.85 )	-27.08 ( 25.03 )	-21.34 ( 39.48 )	-37.38 ( 23.14 )	-6.60 ( 19.43 )	18.00 ( 2.83 )	4.10 ( 24.61 )	-6.30 ( 7.35 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Cohort 1: Placebo

Reporting group description

Subjects received placebo matched to (MEDI0382 100 mcg) SC once daily from Day 1 to Day 7.

Reporting group title

Cohort 1: MEDI0382 100 mcg

Reporting group description

Subjects received MEDI0382 100 mcg SC once daily from Day 1 to Day 7.

Reporting group title

Cohort 2: Placebo

Reporting group description

Reporting group title

Cohort 2: MEDI0382 150 mcg

Reporting group description

Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

Reporting group title

Cohort 3: Placebo

Reporting group description

Reporting group title

Cohort 3: MEDI0382 200 mcg

Reporting group description

Reporting group title

Cohort 4: MEDI0382 200 mcg

Reporting group description

Reporting group title

Cohort 4: Placebo

Reporting group description

Reporting group title

Cohort 5: Placebo

Reporting group description

Reporting group title

Cohort 6: Placebo

Reporting group description

Reporting group title

Cohort 5: MEDI0382 300 mcg

Reporting group description

Reporting group title

Cohort 6: MEDI0382 300 mcg

Reporting group description

Cohort 1: Placebo

Cohort 1: MEDI0382 100 mcg

Cohort 2: Placebo

Cohort 2: MEDI0382 150 mcg

Cohort 3: Placebo

Cohort 3: MEDI0382 200 mcg

Cohort 4: MEDI0382 200 mcg

Cohort 4: Placebo

Cohort 5: Placebo

Cohort 6: Placebo

Cohort 5: MEDI0382 300 mcg

Cohort 6: MEDI0382 300 mcg

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 25 (0.00%)

1 / 26 (3.85%)

0 / 5 (0.00%)

0 / 11 (0.00%)

0 / 12 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

Eye disorders

Diplopia

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 25 (0.00%)

1 / 26 (3.85%)

0 / 5 (0.00%)

0 / 11 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Pneumonia mycoplasmal

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 25 (0.00%)

0 / 26 (0.00%)

0 / 5 (0.00%)

0 / 11 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Cohort 1: Placebo	Cohort 1: MEDI0382 100 mcg	Cohort 2: Placebo	Cohort 2: MEDI0382 150 mcg	Cohort 3: Placebo	Cohort 3: MEDI0382 200 mcg	Cohort 4: MEDI0382 200 mcg	Cohort 4: Placebo	Cohort 5: Placebo	Cohort 6: Placebo	Cohort 5: MEDI0382 300 mcg	Cohort 6: MEDI0382 300 mcg
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 3 (66.67%)	6 / 6 (100.00%)	3 / 3 (100.00%)	5 / 6 (83.33%)	3 / 3 (100.00%)	7 / 7 (100.00%)	22 / 25 (88.00%)	23 / 26 (88.46%)	4 / 5 (80.00%)	2 / 5 (40.00%)	10 / 11 (90.91%)	10 / 12 (83.33%)
Vascular disorders
Haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Phlebitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Thrombophlebitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	2
Early satiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	2	0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	5 / 25 (20.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	5	0	0	0	2	0
Feeling hot
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Injection site discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Injection site erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0	0	0	0
Injection site haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Injection site haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 25 (0.00%)	2 / 26 (7.69%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	5	0	0	2	0	0	0	0
Injection site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	0	2	0
Injection site pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Injection site reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	6	0	0	0	0	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	1	0
Medical device site erosion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Medical device site erythema
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)	2 / 26 (7.69%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	1 / 12 (8.33%)
occurrences all number	1	0	1	1	0	0	3	2	0	0	1	1
Medical device site injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Medical device site irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)	3 / 26 (11.54%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	4	3	0	0	0	0
Medical device site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Medical device site pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)	2 / 26 (7.69%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	3	2	0	0	0	0
Medical device site rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0
Medical device site reaction
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Immune system disorders
Allergic oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	4	0	0	0	0
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Nasal mucosal ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Psychiatric disorders
Restlessness
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Blood pressure diastolic increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Blood pressure increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	2 / 26 (7.69%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	5	6	0	0	0	0
Blood pressure systolic increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	1	0
Body temperature increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
C-reactive protein increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Electrocardiogram st segment depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Heart rate increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Lipase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	2 / 11 (18.18%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	3	1
Injury, poisoning and procedural complications
Burns second degree
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Ligament sprain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Skin abrasion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Atrioventricular block first degree
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0
Atrioventricular block second degree
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0
Extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	1	0	0	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Supraventricular extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Supraventricular tachycardia
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	7	1	1	1	1	1	0	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	1	0	1	0	0	0	0	0	0
Ventricular extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	3	0	0	1	1	0	0	0	0
Ventricular tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0
Arrhythmia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	4 / 25 (16.00%)	5 / 26 (19.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	0	6	6	0	0	2	2
Dizziness postural
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	1
Headache
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	4 / 7 (57.14%)	9 / 25 (36.00%)	2 / 26 (7.69%)	1 / 5 (20.00%)	1 / 5 (20.00%)	3 / 11 (27.27%)	1 / 12 (8.33%)
occurrences all number	0	1	0	3	6	6	10	6	1	1	3	1
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	1
Presyncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Somnolence
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Eye disorders
Abnormal sensation in eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	1
Visual acuity reduced
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	0	0	0
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	6 / 25 (24.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 12 (0.00%)
occurrences all number	0	3	0	0	0	1	9	0	0	0	2	0
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	1 / 25 (4.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	4	1	0	0	0	0
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 7 (14.29%)	6 / 25 (24.00%)	3 / 26 (11.54%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	2	0	1	7	5	1	0	0	1
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	4 / 25 (16.00%)	3 / 26 (11.54%)	1 / 5 (20.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	2 / 12 (16.67%)
occurrences all number	1	0	1	0	8	2	6	4	1	0	2	2
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 7 (42.86%)	7 / 25 (28.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	4 / 11 (36.36%)	2 / 12 (16.67%)
occurrences all number	0	2	0	0	0	3	7	1	0	0	7	2
Eructation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 7 (0.00%)	4 / 25 (16.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	3 / 11 (27.27%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	4	1	0	0	3	0
Faeces discoloured
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0
Faeces hard
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Faeces soft
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)	2 / 26 (7.69%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	2	3	0	0	0	0
Flatulence
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Infrequent bowel movements
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Intra-abdominal haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	3 / 7 (42.86%)	13 / 25 (52.00%)	5 / 26 (19.23%)	1 / 5 (20.00%)	0 / 5 (0.00%)	3 / 11 (27.27%)	5 / 12 (41.67%)
occurrences all number	0	0	0	7	0	4	39	7	2	0	6	7
Pancreatolithiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Regurgitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Salivary hypersecretion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	3 / 7 (42.86%)	8 / 25 (32.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	3 / 11 (27.27%)	1 / 12 (8.33%)
occurrences all number	0	0	0	2	0	8	40	0	0	0	9	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	2	1	0	0	0	0
Dermatitis contact
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	1 / 26 (3.85%)	1 / 5 (20.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	3 / 12 (25.00%)
occurrences all number	0	0	0	0	0	0	1	1	1	0	1	4
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	2
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	3	1	0	0	0	0
Skin reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Renal and urinary disorders
Chromaturia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0
Micturition urgency
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Musculoskeletal and connective tissue disorders
Ankle deformity
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	2 / 25 (8.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	2	2	1	0	0	0	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	1 / 25 (4.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	1	1	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Escherichia urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Gastrointestinal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	4 / 25 (16.00%)	6 / 26 (23.08%)	1 / 5 (20.00%)	1 / 5 (20.00%)	2 / 11 (18.18%)	3 / 12 (25.00%)
occurrences all number	0	1	0	0	0	0	4	7	1	1	2	3
Tonsillitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	6 / 7 (85.71%)	5 / 25 (20.00%)	0 / 26 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	4 / 11 (36.36%)	3 / 12 (25.00%)
occurrences all number	0	0	0	2	1	6	5	0	1	0	4	3
Hypoglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	1 / 26 (3.85%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	2	0	0	0	1
Increased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

26 Feb 2015

Number of anticipated study sites was changed from approximately 3 to 5 to “up to 8” (Section 9.1) • Data for progression from single-ascending dose (SAD) study to Cohort 1 of this multiple-ascending dose (MAD) study were updated (Section 9.4.3.1) • Provision that relevant data for progression from SAD study to the MAD study will be summarized and provided to appropriate regulatory body and central ethics committee was added. Additionally, approval to proceed with MAD study will be obtained from the appropriate regulatory body prior to initiating enrollment was added (Section 9.4.3.1) • Text were added for subject safety (Section 9.4.3.1) • The following text was added for clarification: the decision for progression from Cohort 1 to Cohort 2, and from Cohort 2 to Cohort 3 will be made by Dose Escalation Committee (DEC); relevant data will be summarized and provided to appropriate regulatory body and central ethics committee. And, approval to proceed with Cohort 4 will be obtained from the appropriate regulatory body prior to initiating enrollment (Section 9.4.3.1) • DEC recommendations were updated (Section 9.4.3.1) • Significant vomiting was clarified as “3 or more episodes of vomiting on a single day or across 2 consecutive days, despite adjustment to diet having been made” (Section 9.4.5)• Starting dose reported for SAD study was updated from 30 µg/day to 5 µg/day. Dose rationale was updated. A new table was added (Section 9.2) • A note was added to clarify Inclusion Criterion 9 (about contraception) (Section 9.3.1) • The exclusion criterion “Concurrent participation in another study of any kind is prohibited” was added (Section 9.3.2) • Text was modified to add that an individual subject will not receive any further study drug if that subject has more than 2 symptomatic hypoglycemic events; or persistent hyperglycemia, Section 9.3.3).

14 Aug 2015

Updated and modified text to include a summary of the safety information and statement regarding the current status from the SAD study (D5670C00001) • Changed text to specify change from baseline in glucose and body weight was to be evaluated (Sections 8 and 9.5.1.1) • Objective 1/endpoint 1 were changed to specify change from baseline to be used to evaluate glucose control, blood sample collection parameters at Day 1 were rationalized (Sections 8 and 9.5.1.1) • Clarified that subjects should be treated with a daily dose of statin at baseline. Amended text to include measurement of metformin concentration (Sections 9.5.1.1 and 9.7.1.4) • Analysis of non-esterified fatty acids and beta-hydroxybutyrate were added to the lipid endpoints (Sections 9.5.1.1 and 9.7.1.5) • Number of anticipated clinical sites was increased from 8 to 10. In addition, the inclusion of overweight as well as obese subjects was reflected due to the increased range for body weight eligibility (Section 9.1) • Amended text to lengthen the screening period from 28 days to 42 days • Edited text to clarify that subjects were admitted to the clinic 2 evenings before the receipt of study drug • The Day 1 assessment of MMT and blood samples for glucose metabolism panel were removed from the protocol (Section 9.5.1.2) • Data form SAD study wad added (Section 9.2) • Amended the dose escalation stopping decision and cardiac stopping criteria (Section 9.4.3.1) • Inclusion, exclusion and removal of subjects from therapy or assessment sections were amended (Section 9.3.1, Section 9.3.2, Section 9.3.3) • Schedule of screening procedures (GFR, glucose) and a predose blood sample (Section 9.5.1.2) • Identity of study drug text was modified (Section 9.4.2) • Dose preparation steps were modified • Process of SAE reporting by the Sponsor and the implementation of electronic SAE reporting were modified • Appendix 6 was added • References were updated • Appendix 2 was revised.

10 Oct 2015

Text was amended to reflect a reduction in the maximum dose that was to administered in this study from 400 to 300 µg/day (Section 9.4.3.1) • Amended text to provide the predicted safety margins for the 300 µg/day dose (Section 9.2) • An exclusion criterion excluding subjects with a history of lactic acidosis or ketoacidosis was added (Section 9.3.2) • Text was amended to include collection of finger prick glucose samples 15 minutes prior to and 2 hours after breakfast and before going to bed in addition to the measures taken before and after the mid-day and evening meals to increase glucose monitoring (Section 9.5.1.2) • The footnotes describing the timing of ECG capture were corrected to be consistent with the measurements indicated in the tables (Section 9.5.1.2) • The volume of injection was reduced consistent with the reduction in dose from 400 to 300 µg • The needle gauge was amended from 27G to 29G.

18 Mar 2016

Texts were modified to be consistent with the updated results from SAD study (Section 9.2) • Inclusion criteria related to statin therapy was removed (Sections 9.3.1 and 9.4.7.1) • Exploratory objectives/endpoints and their assessment methods were added (Sections 8.3, 9.5.1.1, 9.5.1.2, 9.7.1.3, and 9.7.1.5) • Study design was changed related to telemetry and return home for subjects in Cohorts 3 and 4 (Sections 9.1 and 9.5.1.2) • Screening window was changed from 42 days to 60 days • Requirement that regulatory approval be obtained “prior to initiating enrollment” in order to proceed with Cohort 4 was changed to “prior to initiating dosing” • Age range for inclusion criteria, upper and lower range of screening HbA1c, and inclusion criterion for HbA1c were changed (Section 9.1 and 9.3.1) • Exclusion criteria for fasting blood glucose was removed; upper range of abnormal systolic and diastolic BP was increased and text was added to note for vital signs criteria and exclusion criteria concerning QRS duration; exclusion criteria regarding subject’s use of weight loss diets/agents, and conditions where MRI is contraindicated were added for Cohort 4 only if site has access to an MRI (Section 9.3.2) • Exclusion criterion of “history of cancer, with exception of non-melanoma skin cancer” was changed to “history of cancer within the last 10 years, with the exception of non-melanoma skin cancer (Section 9.3.2).

27 Apr 2016

The text was changed from “up to 10 study sites” to “approximately 10 study sites” (Section 9.1) • The study design was reverted to state that subjects will be admitted to and remain in the unit for all doses and all dose levels during the up-titration period. Relevant text was modified to reflect the reversion in study design (Section 9.5.1.2) • The age range for inclusion in the study was changed from 18 through <= 69 years to 18 through <= 65 years and relevant text was modified to reflect this change (Sections 9.1 and 9.3.1) • The upper range of screening HbA1c was changed from 9.0% to 8.5% (Sections 9.1 and 9.3.1) • The exclusion criterion of “fasting blood glucose >= 200 mg/dL (11.11 mmol/L)” was reinstated (Section 9.3.2) • The upper range of abnormal systolic BP was decreased by 10 mm Hg for both age groups (< 60 years old, >= 60 years old), and the upper range of abnormal diastolic BP was decreased by 10 mm Hg (Section 9.3.2).

21 Jul 2016

Exploratory endpoint 7 was updated (Sections 9.5.1.1)• Text was changed from “approximately 10 study sites” to “approximately 12 study sites”; “48 subjects” to “approximately 48 subjects” (Section 9.1) • Text was revised to clarify maximum dose in the study (Section 9.1); widen window of pre-dose MRI scan (Table 9.5.1.2-4); criteria of MRI scan (Table 9.5.1.1-1 and Table 9.5.1.2-4); clarification for post dose MRI scan (Table 9.5.1.1-1 and Table 9.5.1.2-4); subjects may be rescreened more than once; subjects will wear the accelerometer on the nondominant wrist continuously for approximately 7 days (Section 9.5.1.3); diluent is not required for Cohort 4 and that a 0.3 mL insulin syringe will be utilized during the in clinic and at-home treatment periods • summary of SAD Study D5670C00001 was revised and Cohort 1-3 safety data from this MAD study was included • Exclusion criteria 35 was revised • Serum chemistries panel note, daily diary training, dose preparation steps were updated.

25 Aug 2016

Text was reverted to specify that subjects may be rescreened only once (Section 9.4.3) • Text was reverted to state that additional subjects may be screened and available to ensure that a sufficient number of subjects are randomized into each cohort (Section 9.4.3).

23 Sep 2016

Text was added/updated to: include Part C of the study and to describe the details of Cohorts 5 and 6 (Sections 9.1, 9.2, and 9.4.1, and Figure 9.1-1); provide rationale for using the 300 μg dose in Part C; add study endpoints related to the addition of Part C, including Cohorts 5 and 6, to the study (Section 9.5.1.1); describe the inpatient periods and clinic visits for Cohorts 5 and 6; concerning the timing of the MMT procedures for Cohorts 5 and 6; to make clear that, for Cohorts 4, 5, and 6, the last PK sample was collected 24 hours after the last dose; provide details of the sample size calculation resulting in 32 subjects in total in Cohorts 5 and 6 (Section 9.7.2); specify 24-hour ABPM was applicable to Cohorts 5 and 6, in addition to Cohort 4 (Section 9.3.2); add Cohorts 5 and 6 to the measuring of body weight during the outpatient periods, and at the 28-day End of Study Visit; describe the sentinel dosing approach for Cohorts 5 and 6 (Section 9.4.3.1); modify description of hypertension; clarify randomization ratio for Cohorts 5 and 6; include 5-day up-titration periods for Cohorts 5 and 6; • 300 μg results were added to the table, and human PK parameters were updated (Section 9.2 and Table 9.2-1) • Number of subjects was increased from 75 to 107 (Sections 9.1 and 9.2) • ‘Cohort 4’ was removed from description of analysis of efficacy endpoints • Updated the inclusion and exclusion criteria; and safety criteria related to the addition of Part C, including Cohorts 5 and 6, to the study • Modified the C SSRS assessment Cohort 4 table (Table 9.5.1.2-4) and 24-hour ABPM assessment • Procedures for Cohorts 5 and 6, were added (Table 9.5.1.2-6 and Table 9.5.1.2-7).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase1/2, Randomized, Blinded, Placebo controlled, Multiple-ascending-dose Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Overweight and Obese Subjects with a History of Type 2 Diabetes Mellitus

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change From Baseline in Mixed-meal Test (MMT) Glucose Area Under the Concentration-time Curve From Time 0 to 4 hours to the End of Treatment (EOT) (Cohort 4)

Primary: Percent Change From Baseline in Mixed-meal Test (MMT) Glucose Area Under the Concentration-time Curve From Time 0 to 4 hours to the End of Treatment (EOT) (Cohort 4)

Primary: Change From Baseline in Body Weight to the EOT (Cohort 4)

Primary: Change From Baseline in Body Weight to the EOT (Cohort 4)

Secondary: Percent Change From Baseline in MMT Glucose AUC0-4h to the EOT (Cohorts 1, 2, 3, 5, and 6)

Secondary: Percent Change From Baseline in MMT Glucose AUC0-4h to the EOT (Cohorts 1, 2, 3, 5, and 6)

Secondary: Change From Baseline in Body Weight to the EOT (Cohorts 1, 2, 3, 5, and 6)

Secondary: Change From Baseline in Body Weight to the EOT (Cohorts 1, 2, 3, 5, and 6)

Secondary: Change From Baseline in Hemoglobin A1c (HbA1c) to the EOT (Cohorts 4, 5, and 6)

Secondary: Change From Baseline in Hemoglobin A1c (HbA1c) to the EOT (Cohorts 4, 5, and 6)

Secondary: Change From Baseline in Fructosamine to the EOT (Cohorts 4, 5, and 6)

Secondary: Change From Baseline in Fructosamine to the EOT (Cohorts 4, 5, and 6)

Secondary: Change From Baseline in Fasting Glucose prior to MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Change From Baseline in Fasting Glucose prior to MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Percent Change From Baseline in Glucose Area Under the Concentration-time Curve From Time 0 to 24 hours (AUC0-24h) after MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Percent Change From Baseline in Glucose Area Under the Concentration-time Curve From Time 0 to 24 hours (AUC0-24h) after MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Secondary: Number of Subjects With Abnormal Vital Signs and Physical Examination Reported as TEAEs

Secondary: Number of Subjects With Abnormal Vital Signs and Physical Examination Reported as TEAEs

Secondary: Number of Subjects With Abnormal 12 Lead Electrocardiogram (ECG) Reported as TEAEs

Secondary: Number of Subjects With Abnormal 12 Lead Electrocardiogram (ECG) Reported as TEAEs

Secondary: Number of Subjects With Abnormal Clinical Laboratory Reported as TEAEs

Secondary: Number of Subjects With Abnormal Clinical Laboratory Reported as TEAEs

Secondary: Number of Subjects With Any Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score (Cohorts 4, 5, and 6)

Secondary: Number of Subjects With Any Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score (Cohorts 4, 5, and 6)

Secondary: Number of Subjects With Any Suicidal Behaviour as Assessed by C-SSRS Score (Cohorts 4, 5, and 6)

Secondary: Number of Subjects With Any Suicidal Behaviour as Assessed by C-SSRS Score (Cohorts 4, 5, and 6)

Secondary: Terminal Elimination Half Life (t1/2) of MEDI0382 (Cohorts 1, 2, and 3)

Secondary: Terminal Elimination Half Life (t1/2) of MEDI0382 (Cohorts 1, 2, and 3)

Secondary: Accumulation Ratio (Rac) of MEDI0382 (Cohorts 1, 2, and 3)

Secondary: Accumulation Ratio (Rac) of MEDI0382 (Cohorts 1, 2, and 3)

Secondary: Area Under the Concentration Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Area Under the Concentration Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - inf)] of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - inf)] of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Maximum Observed Plasma Concentration (Cmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Maximum Observed Plasma Concentration (Cmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Minimum Observed Plasma Concentration (Cmin) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Minimum Observed Plasma Concentration (Cmin) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Number of Subjects With Positive Anti-drug Antibodies to MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Number of Subjects With Positive Anti-drug Antibodies to MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Percent Change From Baseline in Insulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Percent Change From Baseline in Insulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, 4, 5, and 6)

Secondary: Percent Change From Baseline in Proinsulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Secondary: Percent Change From Baseline in Proinsulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Secondary: Percent Change From Baseline in C-peptide AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Secondary: Percent Change From Baseline in C-peptide AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Secondary: Percent Change From Baseline in Incretin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Secondary: Percent Change From Baseline in Incretin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase1/2, Randomized, Blinded, Placebo controlled, Multiple-ascending-dose Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Overweight and Obese Subjects with a History of Type 2 Diabetes Mellitus